Whi2: a new player in amino acid sensing

Teng, Xinchen; Hardwick, J. Marie

doi:10.1007/s00294-018-00929-9

Cited by 17 publications

(23 citation statements)

References 67 publications

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“…Yeast WHI2 was later rediscovered for similar reasons, because spontaneous WHI2 mutations caused cells to continue growing inappropriately after switching cells to medium with low levels of amino acids . This is because Whi2 is required to suppress TORC1 kinase, the master regulator of cellular responses to nutrient status . Interestingly, knockdown of Kctd13 in neuro2A cells was reported to increase cell proliferation .…”

Section: Kctd Genes Associated With Neurodevelopmental and Neuropsychmentioning

confidence: 99%

“…50 This is because Whi2 is required to suppress TORC1 kinase, the master regulator of cellular responses to nutrient status. 14,15,51 Interestingly, knockdown of Kctd13 in neuro2A cells was reported to increase cell proliferation. 52 Whether KCTD13 or KCTD7 regulates TORC1, or whether this involves cullin-3-dependent protein degradation is not known.…”

Section: Kctd7 Mutations Cause a Severe Neurodevelopmental Disordermentioning

confidence: 99%

“…2,4,5 Thus, disrupted proteostasis required for the delicate balance between protein function versus degradation could potentially underlie neurological disorders now associated with the brain-enriched proteins KCTD3, KCTD7, KCTD13, and KCTD17. This proposed adaptor function for KCTD proteins could potentially underlie the diverse biological processes reported for KCTD proteins, including DNA replication (KCTD10 and TNFAIP1), [6][7][8] transcription inhibition (KCTD1 and KCTD15), 9,10 regulation of Rho GTPases in brain development (KCTD13), 11 suppression of hedgehog signaling (KCTD11), 12 autophagy induction and amino acid signaling to mTORC1 (KCTD11), [13][14][15] and more (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

et al. 2019

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The underlying molecular basis for neurodevelopmental or neuropsychiatric disorders is not known. In contrast, mechanistic understanding of other brain disorders including neurodegeneration has advanced considerably. Yet, these do not approach the knowledge accrued for many cancers with precision therapeutics acting on well‐characterized targets. Although the identification of genes responsible for neurodevelopmental and neuropsychiatric disorders remains a major obstacle, the few causally associated genes are ripe for discovery by focusing efforts to dissect their mechanisms. Here, we make a case for delving into mechanisms of the poorly characterized human KCTD gene family. Varying levels of evidence support their roles in neurocognitive disorders ( KCTD3 ), neurodevelopmental disease ( KCTD7 ), bipolar disorder ( KCTD12 ), autism and schizophrenia ( KCTD13 ), movement disorders ( KCTD17 ), cancer ( KCTD11 ), and obesity ( KCTD15 ). Collective knowledge about these genes adds enhanced value, and critical insights into potential disease mechanisms have come from unexpected sources. Translation of basic research on the KCTD‐related yeast protein Whi2 has revealed roles in nutrient signaling to mTORC1 (KCTD11) and an autophagy‐lysosome pathway affecting mitochondria (KCTD7). Recent biochemical and structure‐based studies (KCTD12, KCTD13, KCTD16) reveal mechanisms of regulating membrane channel activities through modulation of distinct GTPases. We explore how these seemingly varied functions may be disease related.

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Section: Kctd Genes Associated With Neurodevelopmental and Neuropsychmentioning

confidence: 99%

Section: Kctd7 Mutations Cause a Severe Neurodevelopmental Disordermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

et al. 2019

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“…Investigations carried out in the last decade have highlighted analogies and differences among different members from both the structural and the functional points of view. Although the biochemical activities of these proteins are still somehow obscure, the biological characterizations of KCTDs have disclosed their crucial roles in highly diversified processes such as protein ubiquitination and degradation 13,15–17 , binding and modulation of the GABA B receptor 18–22 , autophagy 23 , adipogenesis 24 ( Pirone et al unpublished results ), sleep homeostasis 25,26 and metabolic homeostasis 27 . Not surprisingly, they are also involved in the insurgence of severe pathological states that include epilepsy, cancer, obesity, and skin diseases.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of the scalp-ear-nipple syndrome unraveled by the characterization of disease-causing KCTD1 mutants

Smaldone

Balasco

Pirone

et al. 2019

Sci Rep

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the scalp-ear-nipple (seN) syndrome is an autosomal-dominant disorder characterized by cutis aplasia of the scalp and malformations of breast, external ears, digits, and nails. Genetic analyses have shown that the disease is caused by missense mutations of the KCTD1 protein, although the functional/ structural basis of seN insurgence is hitherto unknown. With the aim of unravelling the molecular basis of the SEN syndrome associated with KCTD1 mutations we here expressed and characterized several disease causing mutants. A preliminary dissection of the protein provides insights into the role that individual domains play in KCTD1 stability. The characterization of SEN-causing mutants indicates that, although the mutation sites are located in distant regions of the BtB domain or of the pre-BtB region, all of them are unable to interact with the transcription factor AP-2α, a well-known KCTD1 biological partner. Notably, all mutations, including the one located in the pre-BTB region, produce a significant destabilization of the protein. The structural role of the pre-BTB region in KCTD1 and other proteins of the family is corroborated by its sequence conservation in orthologs and paralogs. Interestingly, seNcausing mutations also favor the tendency of KCTD1 to adopt structural states that are characterized by the ability to bind the β-amyloid fluorescent dye thioflavin T. The formation of aggregation-prone species may have important implications for the disease etiology. Collectively, these findings provide an intriguing picture of the functional and structural alterations induced by KCTD1 mutations that ultimately lead to disease. Members of the KCTD (Potassium Channel Tetramerization Domain) family represent an emerging class of proteins that play a key role in fundamental physio-pathological processes 1-16. Investigations carried out in the last decade have highlighted analogies and differences among different members from both the structural and the functional points of view. Although the biochemical activities of these proteins are still somehow obscure, the biological characterizations of KCTDs have disclosed their crucial roles in highly diversified processes such as protein ubiquitination and degradation 13,15-17 , binding and modulation of the GABA B receptor 18-22 , autophagy 23 , adipogenesis 24 (Pirone et al. unpublished results), sleep homeostasis 25,26 and metabolic homeostasis 27. Not surprisingly, they are also involved in the insurgence of severe pathological states that include epilepsy, cancer, obesity, and skin diseases. A number of these pathologies are generated by mutations of KCTD proteins whose structural interpretations have been scarcely investigated 28,29. In particular, the allelic deletion of human KCTD11 at chromosomal location 17p13.2 has been found in medulloblastoma 30,31 whereas single nucleotide polymorphisms (SNPs) of KCTD10 (i5642G > C and V206VT > C) are associated with altered concentrations of HDL cholesterol in subjects with high levels of carbohydrate intake 9,32. It has been...

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“…WHI2 encodes a protein with phosphatase activator activity that forms a complex with the plasma membrane Psr1 phosphatase and is localized at the cell periphery. It is involved in multiple processes, including cell cycle regulation, cell proliferation, the general stress response, endocytosis, organization of the actin cytoskeleton, and amino acid sensing (Saul and Sudbery 1985;Radcliffe et al 1997;Chen et al 2018;Teng and Hardwick 2019). Whi2 is required for full activation of STRE-mediated gene expression via dephosphorylation of the transcription factor Msn2 (Kaida et al 2002), which is important for proper degradation of misfolded proteins (Comyn et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Unique genetic basis of the distinct antibiotic potency of high acetic acid production in the probiotic yeast Saccharomyces cerevisiae var. boulardii

et al. 2019

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The yeast Saccharomyces boulardii has been used worldwide as a popular, commercial probiotic, but the basis of its probiotic action remains obscure. It is considered conspecific with budding yeast Saccharomyces cerevisiae, which is generally used in classical food applications. They have an almost identical genome sequence, making the genetic basis of probiotic potency in S. boulardii puzzling. We now show that S. boulardii produces at 37°C unusually high levels of acetic acid, which is strongly inhibitory to bacterial growth in agar-well diffusion assays and could be vital for its unique application as a probiotic among yeasts. Using pooled-segregant whole-genome sequence analysis with S. boulardii and S. cerevisiae parent strains, we succeeded in mapping the underlying QTLs and identified mutant alleles of SDH1 and WHI2 as the causative alleles. Both genes contain a SNP unique to S. boulardii (sdh1 F317Y and whi2 S287 *) and are fully responsible for its high acetic acid production. S. boulardii strains show different levels of acetic acid production, depending on the copy number of the whi2 S287 * allele. Our results offer the first molecular explanation as to why S. boulardii could exert probiotic action as opposed to S. cerevisiae. They reveal for the first time the molecular-genetic basis of a probiotic action-related trait in S. boulardii and show that antibacterial potency of a probiotic microorganism can be due to strain-specific mutations within the same species. We suggest that acquisition of antibacterial activity through medium acidification offered a selective advantage to S. boulardii in its ecological niche and for its application as a probiotic.

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Whi2: a new player in amino acid sensing

Cited by 17 publications

References 67 publications

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

Molecular basis of the scalp-ear-nipple syndrome unraveled by the characterization of disease-causing KCTD1 mutants

Unique genetic basis of the distinct antibiotic potency of high acetic acid production in the probiotic yeast Saccharomyces cerevisiae var. boulardii

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